6994
J . Am. Chem. SOC. 1983, 105, 6994-6996
ring system is most commonly constructed by reduction of the corresponding pyridinium salt or from 4-piperidone p r e c u r s ~ r s . ~ J ~ The cyclization approach reported here has the advantage of complete regiocontrol of the double-bond position and, moreover, should be of particular use for preparing 1-aryl-substituted tetrahydropyridines, which are not generally available from pyridine precursors. Two mechanisms can be considered for these cyclization reactions (Scheme I). The simplest is direct cyclization of iminium ion 15 to 6, presumably via a fi-silyl cation intermediate 16." Alternatively, 15 could undergo cationic am-Cope rearrangement12 to allylsilane iminium ion isomer 17, which then cyclizes to 6."-14 Two experiments demonstrate that cationic am-Cope equilibration occurs more rapidly than cyclization. First, treatment of ( Z ) vinylsilane amine 14 in refluxing acetonitrile for 1.2 h with formaldehyde containing a trace of formic acid gave a 6:1:3 mixture of l-isobutyl-1,2,5,6-tetrahydropyridineand the (2)and (E)-methylated amines 1S4and 19: respectively. Since 14 does E isomerization in the absence of formnot undergo Z aldehyde,I5 the loss of stereochemistry when formaldehyde is present implies equilibration of 15 and 17 (R = i-Bu). Conclusive evidence for the facile formation of a rearranged allylsilane comes from treatment of 20 with paraformaldehyde and camphorsulfonic acid (0.95 equiv in refluxing ethanol). This reaction did not yield tetrahydropyridine 21 but rather pyrrolidine 23,,J6 which arises from intramolecular Mannich cyclization12of allylsilane iminium ion 22.
-
and glutarimide with the appropriate vinylsilane a l c o h ~ l .Re~ duction (NaBH,, MeOH, 0 0C)17$19 of 24 (R = H, n = 1 or 2) to the hydroxy lactam, followed by cyclization at 25 "C in trifluoroacetic acid afforded indolizidine 25, and quinolizidine 26,, in 92% and 91% yields, respectively. The Elaeocarpus alkaloids, elaeokanine B (28) and A (29),2O,*'could be easily assembled using this chemistry. Thus, reductionI9 of 24 (R = Br) and cyclization of the resulting hydroxy lactam in refluxing trifluoroacetic acid provided the bromoindolizidine 27, in 63% yield. This reaction constitutes the first report of the use of a 1-substituted vinylsilane terminator and, importantly, yields directly an alkene product regioselectively functionalized for subsequent transformations. Hydride reduction (LiA1H4) of 27 followed by bromine-lithium exchange (sec-BuLi, -78 "C, THF) and reaction of the derived alkenyllithium with butanal gave elaeokanine B (28)20,2'as a 1:l mixture of alcohol diastereomers in 58% overall yield from 27. Oxidation of 28 as described by Weinreb*l provided elaeokanine A (29), which showed spectral properties identical with those of natural materiaI.20.21 Acknowledgment. Financial support from the National Institutes of Health (Grant GM-30859 and NRSA-GM-08 155 to G.P.M.) and the Camille and Henry Dreyfus Foundation (teacher-scholar award to L.E.O.) is gratefully acknowledged. We particularly thank Professor S. Weinreb for providing comparison spectra of racemic elaeokanines A and B. NMR and mass spectra were determined with spectrometers purchased with the assistance of N S F Departmental Instrumentation Grants. Supplementary Material Available: Copies of the 250-MHz 'H NMR spectra for new compounds 6-13,23, and 25-29 (12 pages). Ordering information is given on any current masthead page.
Related cyclizations to form unsaturated azabicyclics, which utilize acyliminium ion initiators," are illustrated in eq 1. Imides
OH
SiMe3
24
25, n = l , R = H 26, n = 2 , R = H 2 7 , n= I , R = B r
28,R=EHCH2CHzCH3
R
(19) Chamberlin, A. R.; Chung, J. Y. L. J . Am. Chem. SOC.1983, 105, 3653-3656. (20) Johns, S. R.; Lamberton, J. A. In 'The Alkaloids"; Manske, R., Ed.; Academic Press: New York, 1973; Vol. 14, p 325. (21) For a recent synthesis and references to other synthetic work in this area, see: Khatri, N. A,; Schmitthenner, H. F.; Shringarpure, J.; Weinreb, S . W. J . Am. Chem. SOC.1981, 103, 6387-6393.
Solvent and Intramolecular Proton Dipolar Relaxation of the Three Phosphates of ATP: A Heteronuclear 2D NOE Study
29,R=CCHzCHzCH3
Chin Yu and George C. Levy* 24, were readily prepared by Mitsunobuls coupling of succinimide (10) For two recent examples, see: Bac, N. V.; Langlois, Y. J. Am. Chem. SOC. 1982, 104, 7667-7669. Evans, D. A,; Mitch, C. H. Tetrahedron Lett. 1982, 23, 285-288. (1 1) Electrophilic reactions of vinylsilanes and allylsilanes have been dis:ussed in detail, see: Weber, W. P. "Silicon Reagents for Organic Synthesis"; Springer Verlag: Berlin, 1983. Colvin, E. 'Silicon in Organic Synthesis"; Butterworths: London, 1981. (12) For recent examples and leading references, see: Overman, L. E.; Kakimoto, M.; Okazaki, M.; Meier, G. P. J . Am. Chem. Soc., in press. Dverman, L. E.; Sworin, M. Tetrahedron 1981, 37, 4041-4045. (13) For a recent example and leading references to intramolecular cy:lization reactions of allylsilanes, see: Trost, B. M.; Remuson, R. Tetrahedron Lett. 1983, 24, 1129-1 132. (14) Cationic cyclizations of iminium ions produced by cationic aza-Cope .earrangements are well-known, see, inter alia: Rischke, H.; Wilcock, J. D.; Winterfeldt, E. Chem. Ber. 1973, 106, 3106-3118. Overman, L. E.; Kakinoto, M . J . Am. Chem. SOC.1979, 101, 1310-1312 and ref 12. Hart, D. J.; rsai, Y.-M. Tetrahedron Lett. 1981, 22, 1537-1570. Nossin, P. M. M.; Speckamp, W. N. Zbid. 1981, 22, 3289-3292. (15) (Z)-Alkene 14 was recovered unchanged (86% yield) when heated for 17 h in refluxing acetonitrile in the presence of 0.95 equiv of camphorsulfonic icid. (16) Isolated as the corresponding~. primary alcohol, formed by NaBHa .eduction, in 73% yield. (17) For a recent brief review, see: Speckamp, W. N. R e d . Trao. Chim. Pays-Bas 1981, 100, 345-362. (18) Mitsunobu, 0.;Wada, M.; Sano, T. J . Am. Chem. SOC.1972, 94, 579-68 1.
0002-7863/83/ 1505-6994$01.50/0
N.I.H. Biotechnology Research Resource for Multi-Nuclei NMR and Data Processing Department of Chemistry, Syracuse University Syracuse, New York 13210 Receiaed July 15, 1983 The nuclear Overhauser effect (NOE) arises from changes in nuclear spin populations resulting from dipolar relaxation in the presence of double irradiation.' Because it is related to (rAB)-6, where rABis the distance between two dipolar coupled spins, A and B, nuclear Overhauser effects can provide valuable molecular structure information for solutions of organic and biological molecules. Due to their inverse dependence on the sixth power of rAB, most reports of NOE arise from intramolecular relaxation. However intermolecular effects have been noted.2-6 (1) Noggle, J. H.; Schirmer, R. E. "The Nuclear Overhauser Effect"; Academic Press: New York, 1971. (2) Kaiser, R. J . Chem. Phy. 1965, 42, 1838. (3) Chan, S . I.; Kreishman, G. P. J . Am. Chem. SOC.1970, 92, 1102. (4) Levy, G. C.; Cargioli, J. D.; Juliano, P. C.; Mitchel, T. D. J . Am. Chem. SOC.1973, 95, 3445. (5) Yuhasz, S . C.; Kan, L.; Ts'o, P. 0. P. In 'Conversation in Biomolccular Sterodynamics 111" Sarma, R. H., Ed.; Academic Press: New York, 1983; page 50. (6) Bacon, M.; Maciel, G. E.; Musker, W. K.; Scholl, R . J . Am. Chem. SOC.1971, 93, 2537.
0 1983 American Chemical Society
Communications to the Editor
J . Am. Chem. SOC.,Vol. 105, No. 23, 1983 6995 Y
I/ a
E
Figure 1. Pulse sequence for the J i P { l H \ heteronuclear 2D NOE (HOESY) experiment.
Ernst et aL7-l0 developed a homonuclear 2D experiment to observe NOE phenomena, which is able to resolve many individual spin NOE effects with a single instrument setting." Jacobson12 used this technique to observe homonuclear 31P-31Pdipolar interactions in the ATP molecule. In this communication, we propose a heteronuclear 2D experiment13 (HOESY) to elucidate dipolar interactions between phosphorus and intramolecular and intermolecular protons. ATP (adenosine triphosphate) plays an essential role in the metabolism of living organisms. However analysis of 31Prelaxation in the ATP molecule is not trivial due to the following factors: (a) 31Prelaxation for the three non-proton-bearing phosphorus nuclei may occur via a mix of mechanisms including dipolar, chemical shift anisotropy (CSA), spin rotation (SR), and dipolar-paramagnetic, in cases where metal ions having unpaired spins are bound to the molecule; (b) the interplay of these relaxation mechanisms is complex, depending on the magnetic field of the instrument, solvent, concentration, sample purity, etc.; (c) other complications are possible including spin diffusion in the 31P manifold and cross relaxation terms associated with CSA and proton and phosphorus dipolar r e l a ~ a t i o n . ' ~ JFurthermore, ~ the 31P{lH]dipolar relaxation contributions in ATP can be difficult to assign, since no proton is directly bonded to the phosphorus atoms. This latter point is particularly true at the high magnetic fields most useful to biological N M R , where dipolar relaxation of ATP is largely displaced by chemical shift anisotropy. For example, Brauer and SykesI5 reported that at 162.0 MHz, CSA accounts for 85%, 82%, and 78% of the total rate of spin-lattice relaxation of the a-, p-, and y-phosphate resonances in ATP bounded to nitrated G-actin. The pulse sequence for heteronuclear 2D NOE (HOESY) experiments is shown in Figure 1 . In principle, this is similar to the homonuclear 2D N O E experiment, except that the 180° (31P)pulse removes scalar interactions between 'H and 31P,so that only cross relaxation through dipole-dipole (1H-31P) interactions leads to exchange of magnetization between ' H and 31P during the mixing period A. The interval A is kept fixed, and the signal is recorded as a function offZ right after a 90° observe pulse. By using the general 2D principle, data sets (FIDs) were created, with constant t , (acquisition time) while linearly increasing t l (evolution time). A two-dimensional Fourier transformation of the data matrix then produces the desired frequency domain spectrum.I6 ATP was purchased from Sigma. The 0.5 M solutions were prepared in 15% D 2 0 phosphate buffer (pH 5.2) and 100% D 2 0 buffer (by repeated lyophilization) with treatment of Chelex 100 (7) Kumar, A.; Ernst, R. R.; Wuthrich, K. Biophys. Chem. Soc. 1970.92, 1102. ( 8 ) Macura, S.; Wuthrich, K.; Ernst, R. R. J . Ma@. Reson. 1982, 46,269. (9) Macura, S.; Haung, Y.; Suter, D.; Ernst, R. R. J . Mugn. Reson. 1981, 43, 256. (IO) Macura, S.; Ernst, R. R. Mol. Phys. 1980, 41, 95. (11) Bosch, C.; Kumar, A,; Bauman, R.; Ernst, R. R.; Wuthrich, K. J . Magn. Reson. 1981, 42, 159. (12) Jacobson, L. J . Magn. Reson. 1982, 49, 522. (13) While our work was in progress we learned of a report of this new technique and its application to protonated carbons in 2-bromobutane: Rinaldi, P. L. J . Am. Chem. SOC.,1983, 105, 5167. (14) Werbelow, L. G.;Grant, D. M. In 'Advances in Magnetic Resonance"; Waugh, J. S., Ed.; Academic Press: New York, 1977; pp 188ff. (15) Brauer, M.; Sykes, B. D. Biochemisrry 1981, 20, 6767. (16) Aue, W. P.; Bartholdi, E.; Ernst, R. R. J. Chem. Phys. 1976, 64, 2229.
il
-J
I' Figure 2. Contour plot of HOESY experiment for 0.5 M A T P in phosphate buffer ( 8 5 % H,O/ 15% D 2 0 ) . Spectral acquisition parameters: 0,222-s acquisition time, 2300-Hz sweep width in thef,("P) dimension, and 0.5s mixing time; 64 spectra (64 scans each) were accumulated with t l incremented to provide the equivalent of a 1950-Hz sweep width in the f l dimension. Zero filling was executed once (to 128) along the f l dimension to give better digital resolution. Conventional ) ' P and ' H (in 100% D20) ID spectra are shown along the f2 and f i dimensions, respectively. Inorganic phosphate is folded inf2 and labeled a s (inorg),.
(Bio Rad Laboratories). Data were acquired at 145.8 MHz on Bruker WM-360 WB spectrometer (equipped with a Aspect-2000 broad-band probe. The 90° pulse width computer) in a IO-" for 'H was carefully calibrated with the method described by BaxI7 to be 124 p . In order to separate the positive and negative modulation frequencies (hence quadrature detection in f,)and suppress the unwanted axial peaks,18 four-step phase cycling was used, and it was further expanded to 16 cycles by incrementing the phases of all proton and phosphorus pulses, as well as receiver, by 90° each time to cancel out the image alongf, = 0 axis. Since quad detection operated on fl, the proton transmitter frequencies were set to the center of the 'H chemical shift region of interest to minimize the required acquisition frequency and amount of data storage space, as well as to optimize dec0up1ing.l~ In order to maximize the efficiency of the experimental time with respect to sensitivity, the preparation period D1 was set to be 1.3 times the mean proton TIzo(those having dipolar interactions with phosphorus). Because cross relaxation between phosphorus and protons occurred during the mixing period, A was set to be of the order of TI of these proton^.^ Shifted sinebel12' and Lorentzian digital filtering functions were applied infl and f 2 dimensions, respectively. Figure 2 shows the contour plot of the HOESY experiment on 0.5 M ATP (15% D 2 0 ) . The normal one-dimensional 31Pand ' H spectra are also shown, along their respective chemical-shift axes. All the cross peaks in Figure 2 originate from heteronuclear dipolar interactions. All three phosphates in ATP show intense cross peaks with the H 2 0 (HOD) signal. This means there are strong dipolar interactions between solvent protons and the phosphorus nuclei. The terminal (y) phosphorus, apparently most accessible to the water, has the strongest cross peak and hence intermolecular dipolar interactions. The a phosphorus shows reduced intermolecular dipolar interactions and also intramolecular dipolar interactions with the sugar 5'-hydrogens. The @ phosphorus shows only low-level dipolar interaction with solvent protons. Figure 3 shows the contour plot of a similar HOESY experiment for 0.5 M ATP in 100% D 2 0 buffer. In this instance, all (17) Bax, A. J . Magn. Reson. 1983, 52, 76. (18) Bax, A. 'Two-dimensional nuclear magnetic resonance in liquid"; Reidel: Boston, 1982; Chapter 2. (19) Bax, A.; Morris, G. A. J . Mugn. Reson. 1981, 42, 501. (20) Waugh, J . S. J . Mol. Spectrosc. 1970, 35, 298. (21) Wanger, G.; Wuthrich, K.; Tschesche, H. Eur. J . Biochem. 1978,86, 67.
6996
J . A m . Chem. Soc. 1983, 105, 6996-6997 a
I
Scheme I. Intramolecular Cycloadditions of 6-Methyl-6-(4,6-hep tadieny1)fulvene
B
n / \rH
A
n
1
4 (23%) Scheme 11. Preparation and Cycloadditions of Fulvenes Linked to Electron-Rich Dienes" I1
/\/Me
u1
Figure 3. Contour Plot of the HOESY experient for 0.5 M A T P in phosphate buffer (100% DzO,repeated lyophilizations). Acquisition
/ 6
parameters, same as figure 2.
the cross peaks between phosphorus and protons in the solvent disappear (there is no significant concentration of water protons remaining). Cross peaks arising from H-5' sugar and H-8 base protons to a-phosphorus and from H-5' to P-phosphorus are easily observed. The heteronuclear 2D NOE experiment presented here provides information to analyse the dipolar relaxation behavior of the nonprotonated phosphorus atoms in ATP. This HOESY experiment should prove useful for evaluation of molecular conformation and also for studies of solventsolute interactions. The observed nucleus is of course not restricted to phosphorus, and this technique is expected to have significant potential in studies of peptides (I5N, I%), metalloenzymes (M), and metabolic studies (31P,I3C).
Acknowledgment. We thank Dr. Ad Bax for thoughtful contributions and discussions; Dr. E. Garcia provided experimental assistance. This work was supported by NSF Grant C H E 8105109 and N I H Grants R R 01317 (Division of Research Resources) and G M 29778. Registry No. Phosphate, 14265-44-2; phosphorus, 7723-14-0 hydrogen ion, 12408-02-5; adenosine triphosphate, 56-65-5.
Selective Intramolecular [6 Aminodienylfulvenes
yc;.lv
v w viivii v w viivii
a:n-5, R-H b: 17-6, R=H c:n-5, R=Me
i
)eJ
/ 8
'CHO
10
9 a-c: X=NE12 c' :X=OSiMe3, n=5, R=Me
a Reagents (yields): (i) PCC, CH2C1, (a, 62%; b, 41%); (ii) Ph,P+CH,CH(OCH,CH,O) Br-, t-BuOK, THF (a, 47%; b, 43%; c, 5 3 4 ) ; (iii) PCC, CH2C1, (a, 81%; b, 72%); (iv) 0,, then KI, HOAc (30%); (v) C,H,, E t 2 N H , MeOH (a, 50%; b, 72%); (vi) C,H,, KOH, T H F , MeOH (c, 41%); (vii) 5% aqueous HC1, T H F (a, 85%; b, 85%; c, 81%); (viii) Et,NH, K,CO,, PhH, SA molecular sieves (a, 5 5 % ; b, 46%; c, 54%);14 (ix) Me,SiCl, ZnCl,, Et,N(C).
+ 41 Cycloadditions of
Tse-Chong Wu, Jiri Mareda, Y. N. Gupta, and K. N . Houk* Department of Chemistry, University of Pittsburgh Pittsburgh, Pennsylvania 15260 Received June 6, 1983 We recently reported several intramolecular [6 + 41 cycloadditions involving fulvenes as the 6 a electron components and o-xylylenes as the 4 a components.' We have now investigated similar reactions involving acyclic dienes as 4 a electron components and have found that predictable substituent effects transform a despicably unselective reaction into a delightfully specific [ 6 41 cycloaddition. The hydrocarbon dienylfulvene 1 was prepared in 74% yield by the reaction of sodium cyclopentadienide with 6,8-nonadien2-one.* Thermolysis of a 1% solution of 1 in toluene at 210 OC for 48 h produces the complex mixture of thermally allowed cycloadducts shown in Scheme I. The different types of adducts were separated chromatographically, but the stereoisomers have
+
(1) Gupta, Y. N.; Doa, M. J.; Houk, K. N. J . Am. Chem. SOC.,1982, 104, 7336. (2) Gras, J.-L.; Bertrand, M. Tetrahedron Lett. 1979, 4549.
0002-7863/83/ 1505-6996$01.50/0
not been ~ e p a r a t e d . The ~ trimethylene connecting chain can be seen to promote the [6 + 41 and spiro-[4 + 21 cycloaddition modes, since the intermolecular reactions of alkyl-substituted dienes with fulvenes give only Diels-Alder adducts analogous to 4.4 Theoretical predictions and experimental studiesS of intermolecular cycloadditions of dienes to fulvenes have shown that an electron donor at one terminal carbon of the diene provides sufficient nucleophilicity at the other diene terminus to promote (3) The product compositions were determined by N M R spectroscopy. The [6 + 41 adduct 2 is a mixture of cis and trans isomers and cyclopentadiene isomers,' while the [4 + 21 adducts are cis-trans mixtures. Details will be reported in a full paper. (4) Houk, K. N.; Luskus, L. J. J . Org. Chem. 1973, 38, 3836. ( 5 ) Houk, K. N., Sims, J.; Watts, C. R.; Luskus, L. J. J . A m . Chem. SOC. 1973, 95, 7301. Houk, K. N.; George, J. K.; Duke, R. E., Jr. Tetrahedron 1974, 30, 523. Houk, K. N. Acc. Chem. Res. 1975, 8, 361. Dunn, L. C.; Chang, Y.-M; Houk, K. N., J . Am. Chem. SOC.1976, 98, 7095. Dunn, L. C.; Houk, K. N. Tetrahedron Lett., 1978, 3411. Mukherjee, D.; D u m , L. C.; Houk, K. N. J . Am. Chem. SOC.1979, 101, 251. Gupta, Y. N.; Mani, S. R.; Houk, K. N. Tetrahedron Lett. 1982,23,495. Bimanand, A. Z.; Gupta, Y. N.; Doa, M. J.; Eaton, T. A.; Houk, K. N.; Fronczek, F. R. J . Org. Chem. 1983, 48, 403. (6) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647.
0 1983 American Chemical Society
